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TU/e technische universiteit eindhoven
[email protected] December 2009
NOVEL PROCESS WINDOWSDoors to More Cost-Efficient and Environmentally
Benign Processes and New Products
DBU Workshop “Novel Process Windows”Osnabrück, 10.12.09
Volker [email protected]; [email protected]
1 Eindhoven University of TechnologyDepartment of Chemical Engineering and Chemistry
2 Institut für Mikrotechnik Mainz GmbHChemical Micro and Milli Process Technologies
3 Technische Universität Darmstadt Technical Chemistry
TU/e technische universiteit eindhoven
[email protected] December 2009
Starting Position – ACS-Novel Chemistry / Microwaves / Microreactors / Flash Chemistry
Dissemination & Exploitation - Conferences, Symposia, Research Projects, Products
Novel Process Windows – Concept and Research Cluster
Applications and Demonstrations– Literature review
Cost and Environmental Impacts– Cost and Life-Cycle Analysis
CONTENTS
TU/e technische universiteit eindhoven
[email protected] December 2009
Starting Position– ACS-Novel Chemistry / Microwaves /
Microreactors / Flash Chemistry
TU/e technische universiteit eindhoven
[email protected] December 2009
NEW CHEMISTRY ROADMAP, ACS- JOE ZOELLER, EASTMAN KODAK, 2001
A.E. Staley ManufacturingARCO ChemicalAGA GasAir Products & ChemicalsAkzo-NobelAutoclave EngineersBCIBF GoodrichBiofineBOC GasesCelaneseCryo DynamicsDegussaDOW ChemicalDOW CorningDuPontEastman ChemicalElectroluxEltron Research Inc.Fedegari AutoclaviFord Motor CompanyGenentechGE PlasticsGlobal TechnologiesGreat Lakes Chemical CorpGreen Chemistry InstituteIsopro InternationalItochu AviationKellogg, Brown & Root, Inc.…
TU/e technische universiteit eindhoven
[email protected] December 2009
EARLY LITERATURE REVIEWS- HIGH PRESSURE CHEMISTRY
F.-G. Kärner, M. K. Diedrich, A. E. Wigger, 3. Effect of pressure on organic reactions in: Chemistry under extreme or npn-classical conditions. (eds. R. van Eldik, C. D. Hubbard) 1997, John Wiley & Sons, New York
TU/e technische universiteit eindhoven
[email protected] December 2009
• Type A reactions: very fast, < 1 s; mixing controlled• Type B reactions: rapid, 1 s to 10 min; kinetically controlled• Type C reactions: slow, > 10 min; safety and quality issues
21%
23%
6%
2%9%
8%
Type A reactionsType B reactionsType C reactionsRemaining
Big circle: based on kinetics only
Small circle:based on kinetics & phases
• 50% of the reactions to benefitfrom a continuous process
• 63% not suited to current microreactors due to solid carriage
Roberge, D.M., Ducry, L., Bieler, N., Cretton, P., Zimmermann, B. Chem. Eng. Tech. 28, 3 (2005) 318-323
Classification of 86 reactions campaigns carried out at Lonza
SUITABILITY OF REACTIONS
TU/e technische universiteit eindhoven
[email protected] December 2009
TU/e technische universiteit eindhoven
[email protected] December 2009
MICROWAVE ENCASED PROCESSING
{>200oC; >50 bar; <1 s} ‘alike gas-phase chemistry’
High-p,T microreactor protocol
{50-130oC; 1 bar; 2-8 h} Conventional lab batch I
EtO2C Me
NN
SO2 NH2
I
Me
NN
SO2 NH2
20% H2 SO4
MW, 200oC, 5 min
following the routes of microwave assisted continuous synthesis (MAOS)
X = 88%
Reflux, 100oC, 96 hX = 86%
Organ, M.G., Mayer, S., Lepifre, F., M‘Zemba, B., Kathri, J. Mol. Diversity 7 (2003) 211-227.
Temperature [oC] 27 77 127 177 227Rate constant k [s-1] 1.6 x 10-7 4.8 x 10-5 3.5 x 10-3 9.9 x 10-2 1.43Time (90% conversion) 68 days 13.4 h 11.4 min 23.4 s 1.61 sfrom: Kappe, C.O., Stadler, A. Microwaves in Organic and Medicinal Chemistry, Vol. 25 in: Methods and Principles in Medicinal Chemistry (eds.: Mannhold, R., Kubinyi, H., Folkers, G.) Wiley-VCH (2005) pp. 94-95.
k = A exp (-Ea /RT) A = 4 x 1010 mol-1 s-1
Ea = 100 kJ mol-1
TU/e technische universiteit eindhoven
[email protected] December 2009
Comparable yields were obtained for the continuous process, but with much shorter reaction times:
Reaction time reduction at best up to 2000 times; increase in space-time yield by factor 440
0
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0 20 40 60 80 100 120 140Time (min)
Yiel
d(%
)
At reflux conditions
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0 0.18 0.37 0.72 1Time (min)
Yiel
d(%
) Continuous process
Batch process
T= 180oC p= 40 bar
OH
OH
OH
OH
COOHKHCO3 (aq)
V. Hessel, C. Hofmann, P. Löb, J. Löhndorf, H. Löwe, A. Ziogas Org. Proc. Res. Dev. 9, 4 (2005) 479-489
KOLBE-SCHMITT SYNTHESIS: SPEED-UP OF REACTION BY HIGH-p,T PROCESSING
17,350 € / kg
92.20 € / kg
Aldrich sales price 160 € / kg
Novel Process Windows
TU/e technische universiteit eindhoven
[email protected] December 2009
160°C, previous results200°C, previous results
140°C, previous results
6532 16
12 8Residence time (s)
Total flow rate (ml/h)
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140°C, previous results
200°C, previous results
140°C, previous results
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160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results
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65 32 16 12 8
Residence time (s)
5400
4
10800
10700 15400
18300 30750
560
200 C, Projekt250 C, Projekt
160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results
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200°C, previous results
140°C, previous results
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160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results
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Total flow rate (ml/h)
Yiel
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65 32 16 12 8
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10700 15400
18300 30750
560
200 °C, Ölbad, wässrig250 °C,
6064200
Ölbad, wässrigÖlbad, BMIM-HC200 °C,
160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results
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Total flow rate (ml/h)
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140°C, previous results
200°C, previous results
140°C, previous results
65 32 16 12 8
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0 1000 2000 3000 4000 5000Total flow rate (ml/h)
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160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results
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65 32 16 12 8
Residence time (s)
5400
4
10800
10700 15400
18300 30750
560
200 C, Projekt250 C, Projekt
160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results
6532 16
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Total flow rate (ml/h)
Yiel
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200°C, previous results
140°C, previous results
200°C, previous results
140°C, previous results
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Residence time (s)
Total flow rate (ml/h)
Yiel
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)
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Yiel
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160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results160°C, previous results200°C, previous results
140°C, previous results
6532 16
12 8Residence time (s)
Total flow rate (ml/h)
Yiel
d(%
)
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Yiel
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65 32 16 12 8
Residence time (s)
5400
4
10800
10700 15400
18300 30750
560
200 °C, Ölbad, wässrig250 °C,
6064200
Ölbad, wässrigÖlbad, BMIM-HC200 °C,
PROCESS INTENSIFICATION: INCREASE IN SPACE-TIME YIELD BY HIGH-p,T PROCESSING
OH
OH
OH
OH
COOHKHCO3 (aq)
V. Hessel, C. Hofmann, P. Löb, J. Löhndorf, et al. Org. Proc. Res. Dev. 9, 4 (2005) 479-489.V. Hessel, U. Krtschil, P. Löb, A. Stark, et al. Org. Proc. Res. Dev. 13, 5 (2009) 970-982.
Reaction time reduction at best up to 2000 times; increase in space-time yield by factor 3200
4 t / a64200 kg/(m³ h)
4 sFlow chem (9 ml)
Batch (1 l)2 h – 7200 s20 kg/(m³ h)
1 t / a
140°C, (initial)200°C, aq (initial)200°C, aq250°C, aq200°C, IL BMIM-HC
U. Krtschil, V. Hessel, A. Stark, D. Reinhard, Chem. Eng. Technol. 32, 11 (2009) 1774-1789.
TU/e technische universiteit eindhoven
[email protected] December 2009
Jun-ichi Yoshida, Kyoto UniversityJ.-i. Yoshida, A. Nagaki, T. Yamada, ”Flash Chemistry: Fast Chemical Synthesis by Using Microreactors”, Chemistry - A European Journal 14, 25 (2008) 7450 – 7459.
FLASH CHEMISTRY – COMPLEMENTARY TO NOVEL PROCESS WINDOWS
• CET Special Issue„Novel Process Windows; in 11/09
• International DBU Workshop„Novel Process Windows“; in December 10, 2009
• Topical book„Novel Process Windows“, Wiley-VCH; in 2010
TU/e technische universiteit eindhoven
[email protected] December 2009
Novel Process Windows– Concept and Research Cluster
TU/e technische universiteit eindhoven
[email protected] December 2009
NOVEL PROCESS WINDOWS
V. Hessel Chem. Eng. Technol. 32, 11 (2009) 1655-1681.
TU/e technische universiteit eindhoven
[email protected] December 2009
DBU RESEARCH CLUSTER NOVEL PROCESS WINDOWS (April 2007)
MissionNovel process windows with regard to pressure, temperature, concentrationSustainable chemical processes by temperature stable, pressurised microreactors
Technical Targets• High energy efficiency• Minimisation of waste• Clean and inherently safe product makign• Safe and low-emission syntheses• Process intensification (e.g. increase in space-time yield)
Relevant Topics• High-temperature & high-pressure conti routes, e.g. for functionalisation of alkanes• Syntheses in explosive and thermal runaway regimes• Solvent-less and free syntheses• Multi-step syntheses with immediate conversion of instable intermediates
TU/e technische universiteit eindhoven
[email protected] December 2009
New products via new process windows
• OLED materials
• Phenols by Kolbe-Schmitt synthesis
• Chitosan for Pharmaceuticals
• High pressure amination of hydrocarbons
• New ink materials
guided and accompanied by LCA & cost analysesUniversities in co-operation with industry: • Jenpolymers Ltd• Sigma-Aldrich• Heppe Medical Chitosan GmbH,• Pelikan PBS GmbH &CoKG• ASD GmbH, JTT
PROJECT CLUSTER ‚NOVEL PROCESS WINDOWS‘ AT DBU
• KONAROM, sugar melts
• CORA, H2 O2 via membranes+
TU/e technische universiteit eindhoven
[email protected] December 2009
Applications and Demonstrations– Literature review
TU/e technische universiteit eindhoven
[email protected] December 2009
One-flow (‘pot’) multi-step route instead of multiple step-wise processing
D. R. J. Acke, C. V. Stevens, Green Chem. 9 (2007) 386–390.
• Moderate to good yields up to 66%.
• In situ generated HCN produced fromKCN was directly consumed
HO N Hts
I N H
/ EtOHO
H
II
1] -7°C, 4hrs
NHO
III
2] 6N HCl 20°C, 16 hrs., 45°C 4 hrs3] KOH, reflux, 24 hrs.4] 5N HCl to Ph = 7, 0°CHO N
O
ts
1]
HO N
O
ts
OEt
Et
Ia
Ib
HO N
OH
ts
HO N
O
ts2]
Ic'
Ic
NHO
OH
ts
NHOts
Id
Ie
3]
4]
Famous telescoping syntheses
Total synthesis of tropinone - Gassman indole synthesis
X R
OH
R
O
OR2
4
1
n[ ]
R CHO1
NH3
R OH2
CO2R NC4
R O
HBr
3n[ ]
X = O, S NaXH
Ugi synthesis
3,4-diamino-1H-isochromen-1- ones synthesis in microreactor
O
H
O
OH
N
H
O
OH
RNH
C
O
O-
R
N
N
O
O
R H
NHN
O
O
R H
NH2
RNH2 KCNHOAc
New chemical transformations
TU/e technische universiteit eindhoven
[email protected] December 2009
Space-timeyield(mol/m³h)
10 20 30 40 50 60 70 80 90 10010
100
1000
mol / mol (%)Fluorine Toluene
1 E -3 0 ,1 1 0 1 0 0 0 1 0 0 00
5
1 0
1 5
2 0
2 5
M B S I M B S II M F F R L B S
Y [%
]
τ [s ]
SPACE-TIME YIELD – THE REDUCTION OF RESIDENCE TIME
mono-F
Space-timeyield(mol/m³h)
mono-F
Spa
ce-ti
me
yiel
d
• Significant enhancement of space-time yield for the micro- structured reactors compared to the laboratory bubble column
Reaction volume = Active channel volume
CH3
+ F2- HF
CH3
F
CH3F
CH3
F
+ +
Acetonitrile, -16°C
Jähnisch, K., et al..; J. Fluorine Chem. 105, 1 (2000) 117
New chemical transformations
TU/e technische universiteit eindhoven
[email protected] December 2009
‘Lukewarm’ ex-cryogenico processes – MOFFAT-SWERN OXIDATION
T. Kawaguchi, H. Miyata, K. Ataka, K. Mae, J.-i. Yoshida, Angew. Chem. Int. Ed. 44 (2005) 2413 –2416.
S O + (CF3CO2)2O S+ OCOCF3
HOR'
RS+ O
R
R'
OR'
RS+
1st Step
2nd Step
3rd Stepbase
• Side reaction: the Pummerer rearrangement• Processing in batch reactors at very low temperatures (<-50°C)• Processing in a microreactor at temperatures between -20 and 20°C • Three-reaction process - a cascade with the same number of micromixers
• Microreactor yields much higher than batch yields (e.g. 95% opposed to 20%) at very short residence times of 0.01 s
Elevated temperature
TU/e technische universiteit eindhoven
[email protected] December 2009
COPPER-FREE SONOGASHIRA COUPLING
H. Kawanami, K. Matsushima, M. Sato, Y. Ikushima, Angew. Chem. Int. Ed. 46 (2007) 5129 –5132.
H
+I
RR
cat., base
rapid mixing andheating in HPHT-time: 0.012 - 4 s
H2O
• Green process: water-mediated, without organic solvents
• Step-by-step rapid mixing and heating
• Copper-free process without specific ligands for Pd catalyst
• High-pressure and high-temperature water micro processing
• Nearly quantitative yield for only 0.1–4.0 s at 250°C and 16 MPa
• Even at 0.035 s, yield was >96% yield, but decreased to 1.5% at 0.012 s
• No homocoupling
Elevated temperature
TU/e technische universiteit eindhoven
[email protected] December 2009
GLYCOSYLATIONS
D. M. Ratner, E. R. Murphy, M. Jhunjhunwala, D. A. Snyder, K. F. Jensen, P. H. Seeberger, Chem. Commun. 2005, 578–580.
OBnOBnO OAc
OBn
O
CCl3
NHO
OBn
OOBnO
OOO
O
O O
OBn
+OO
O OH
OO
OO
O O
OO
OOAcBnOBnO
OBn
+TMSOTfCH2Cl2
• Batch: good product yields from -60 to -40°C, with some orthoester formation; the optimum being at -60°C and 213 s.
• Microreactor: nearly the same yield at -35 °C and 25.7 seconds
Mannosylation of diisopropylidene galactosewith mannosyl trichloroacetimidate
Elevated temperature
TU/e technische universiteit eindhoven
[email protected] December 2009
‘Scalding hot’ pressurized ex-reflux processes – BROMINATIONS
P. Löb, H. Löwe, V. Hessel, J. Fluorine Chem. 125, 11 (2004) 1677-1694.
CH3 CH3
Br
CH3
Br
CH2BrBr2
+ +
CH2
NO2
CH2Br
NO2
Br2
• At high temperature, nearly all bromi-nated species were core-substituted
• At 0°C, side-chain bromination with a selectivity still below 20%
• At 170, 1.9 min and 190°C, 2.4 min, side-chain brominationto benzyl bromide
• Higher conversion (40% to 95%) with temperature and pressure
Elevated temperature
TU/e technische universiteit eindhoven
[email protected] December 2009
NEWMAN-KUART REARRANGEMENT
X. Zhang, S. Stefanick, F.J. Villani, Org. Process Res. Dev. 8, 3 (2004) 455.
NO2
O
NMe2S
NO2
S
NMe2O
170°C90 %
• Industry’s multi-purpose plants have upper temperature limit of 140°C
• Standard microstructured reactors proved safe operation at above 200°C
• Yield of nearly 100% at 170°C > yield by laboratory equipment (90%)
O-(2-nitrophenyl)-N,N-dimethylthiocarbamate to S- (2-nitrophenyl)- N,N-dimethylthiocarbamothioate
Elevated temperature
TU/e technische universiteit eindhoven
[email protected] December 2009
HIGH-p,T WINDOWS FOR TUNING α-KETOAMIDE / AMIDE SELECTIVITY
Murphy, Martinelli, Zaborenko, Buchwald, Jensen Angew. Chem. Intl. Ed. 119, 10 (2007) 1764-1767
Boiling point toluene (atm)
favoured by high pressure (CO) α-ketoamide
favoured by high temperature amide
α-ketoamide
amide
Elevated temperatureElevated pressure
TU/e technische universiteit eindhoven
[email protected] December 2009
HIGH-T FLOW ORGANIC SYNTHESIS
T. Razzaq, T. N. Glasnov, C. O. Kappe, Eur. J. Org. Chem. 2009, 1321–1325.
O OH
Toluene (0.1 M)240 °C, 100 bar1.0 mL/min
N Cl N
O
H
N NO
+NMP (0.04 M)
270 °C, 70 bar0.4 mL/min
Ph OEt
O
Ph OMe
OscMeOH (0.05 M)
350 °C, 180 bar0.5 mL/min
Full conversion and 82% yield within 8 min for direct amination of 2-chloropyridine with morpholine at 270 °C and 70 bar as opposed to reaction times of several days in conventional equipment
• Extended study concerning high-temperature flow organic synthesis • Stainless steel microtubular flow reactor, up to 350°C and 200 bar.• Lower boiling solvents in or near supercritical state with same extreme experimental
environments as high-boiling solvents at reflux or under sealed-vessel MW conditions
Diels–Alder reaction, Newman-Kwart rearrangement, Fischer indole synthesis, Claisen rearrangement, supercritical transesterification, and nucleophilic aromatic substitution (SNAr) of 2-halopyridines with amines
Elevated temperature
TU/e technische universiteit eindhoven
[email protected] December 2009
Nucleophilic aromatic substitution
Capillary microreactor
Fiber-based chip interface Glass high-pressure microreactorFiber-based chip interface
Elevated pressure
HIG-PRESSURE AMINATIONS
TU/e technische universiteit eindhoven
[email protected] December 2009
HIGH-PRESSURE DIELS-ALDER REACTIONS
Stereoselectivity of Diels-Alder reactions
Volume difference of endo and exo transition states Minimised structures for reaction volumes ΔV
7 + 8 Conversion [%] endo (9) / exo (10) ratio1 bar 600 bar 1 bar 600 bar
aa 35 66 66:34 59:41ab 35 55 55:45 52:48ac 40 62 62:38 57:43
ba 57 57 57:43 57:43bb 55 54 40:60 39:61bc 59 58 55:45 54:46
Elevated pressure
TU/e technische universiteit eindhoven
[email protected] December 2009
ACETONE HYDROGENATION
K. Pimparkar, R. Lin, R. Y. Ofoli, J. E. Jackson, S. Obare, D. J. Miller, High Pressure Catalytic Hydrogenation of Acetone in a PDMS Based Recirculating Microreactor System, Proceedings of the AIChE Annual Meeting 2008, Philadelphia, November 15-21, 2008.
• Usually, polymeric microreactors cannot easily be operated at high pressure due to lacking mechanical strength
•This is overcome by a specialty construction embedding the microreactor in a high-pressure Parr reactor enabling operation up to 725 psi
• At 650 psi hydrogen pressure, 20% conversion with no byproduct formation
Catalytic hydrogenation of acetone to isopropanol over Ru/C catalyst
O OHH2
Ru/C catalyst
Elevated pressure
TU/e technische universiteit eindhoven
[email protected] December 2009
Formation of carbamic acid of N- benzylmethylamine
K. Pimparkar, R. Lin, R. Y. Ofoli, J. E. Jackson, S. Obare, D. J. Miller, High Pressure Catalytic Hydrogenation of Acetone in a PDMS Based Recirculating Microreactor System, Proceedings of the AIChE Annual Meeting 2008, Philadelphia, November 15-21, 2008.
Specialty micro-reactor chip designed for high-pressure chemistry made out of several in-plane fiber-based interface geometries• Upper pressure limit of 180–690 bar
NH + (l) CO2
CD2Cl2 N
OHO
• Carbamic acid not formed at 10 bar (166 s), but formed up to 300 bar at 8 s
• Up to 400 bar no destruction of the chips, no product formed due to too small residence times
Formation of carbamic acid from N-benzylmethylamine and CO2
Elevated pressure
TU/e technische universiteit eindhoven
[email protected] December 2009
CONTACTING OF THE DIFFERENT EDUCTS WIHT BROMINE (1:1) IN A GLASS MICRO MIXER
toluene thiophene
Br2 [ml/h] / Educt [ml/min]:
meta-nitrotoluene
18.6 / 42.824.5 / 49.8
18.4 / 28.4
reaction speed
formation of gaseous hydrogen bromide
Solvent-free
TU/e technische universiteit eindhoven
[email protected] December 2009
ANHYDRIDE ESTERIFICATION
F. Benito-Lopez, R. M. Tiggelaar, K. Salbut, J. Huskens, R. J. M. Egberink, D. N. Reinhoudt, H. J. G. E. Gardeniers, W. Verboom, Lab Chip 7 (2007) 1345–1351.
O
O
O
+ MeOHO
OH
O
O
• Normal high-pressure operation led to 53-fold increase at 110 bar and 60°C as compared to batch experiments at 1 bar and 60°C
• Supercritical CO2 processing led to a 5400-fold increase
• Reason: changes in activation energies, possibly due to pressure-induced changes in reaction mechanisms, negative molar activation volume, andsurface (catalytic) effects.
Supercritical processing with CO2 up to 110 barAlternative solvents
TU/e technische universiteit eindhoven
[email protected] December 2009
HAZARDOUS REACTIONS FLUORINATIONS WITH REACTIVE AGENTS
M. Baumann, I.R. Baxendale, L.J. Martin, S.V. Ley, Tetrahedron 65 2009, 6611–6625.
O
N
N
OCN
OO
O
O
N
N
OCN
O
O
FF
DAST
• DAST, for example, is volatile, reacts violently with water and readily undergoes dismutation to SF4 and (Et2 N)2 SF2 at temperatures above 90°C
• A series of methods including nucleophilic fluorination, electrophilicfluorination and trifluoromethylation in a commercial capillary flow reactor
• Products with purities >95% and at yields up to 95%, eliminating purification• Pressurised operation through back-pressure regulators led to superheated processing to accelerate the reactions
Dedicated fluorinations with diethyl-amino- sulfur trifluoride (DAST), (1-chloro-methyl- 4-fluoro-1,4-diazo-niabicyclo-[2.2.2]octane), bis(tetrafluoroborate) (Selectfluor®), and and trimethylsilyl trifluoromethane (TMS- CF3, Ruppert’s reagent)
Hazardous reagents
TU/e technische universiteit eindhoven
[email protected] December 2009
DIAZOMETHANE CONVERSION
M. Struempel, B. Ondruschka, R. Daute, Annegret Stark, Green Chem. 10 (2008) 41–43.
• Generation of diazomethane from a commercial precursor, Diazald®
• Consumed at-site consumed by reaction
• Benzoic acid methyl ester at a yield of up to 75% at 0 and 50°C
• 2.5 mol d-1 of diazomethane can be produced with a single microreactor at a total flow rate of 840 ml h-1
Np-TosN
CH3
O
+ KOH CH2 N+ N-
Ph OCH3
O-p-TosOK
-HOH
+PhCO2H
-N2
Hazardous reagents
TU/e technische universiteit eindhoven
[email protected] December 2009
Trimethylaluminium mediated amide bond formation
T. Gustafsson, F. Pontén, P.H. Seeberger, Chem. Commun. 2008, 1100–1102.
Cl
O
+Cl
O
CO2Et
OOEt
OEtO
O
Cl
NNCO2Et
ClCl
Cl
NN
ClCl
NH
O
N
a
b
c
• Aluminium-mediated amine activation with trimethylaluminium, highlypyrophoric and difficult to handle safely in larger volumes
• The aluminium–amide intermediate is unstable at elevated temperatures • Batch reaction at 4 and 16 h• Combined microwave and microreactor operation at 2 min• Applied for the synthesis of rimonabant and efaproxiral at 49% yield• Rimonabant is anti-obesity drug & central cannabinoid receptor antagonist
Hazardous reagents
TU/e technische universiteit eindhoven
[email protected] December 2009
AUTOCATALYTIC NITRATION OF PHENOL
L. Ducry, D. M. Roberge, Angew. Chem. 117 (2005) 8186–8189.
OHOH
NO2
OHNO2
OH
OH
OH
NO2
NO2OH
O2N NO2HNO3 + + + +
• Thermal runaway behaviour, even at small scale (1 l) an increase of 55 K
• Hot-spot in microreactor was only about 5 K
• Micro processing with largely increased purities (batch: up to 25%, micro-flow: up to 79%), and higher yields (batch: up to 32%, micro flow: up to 77%)
• Micro processing can use concentrated conditions, almost solvent-free and without H2 SO4 or CH3 CO2 H
• Nitration of phenol is different from normal nitrations, because it is catalyzed by nitrous acid and not by the nitronium ion
• Autocatalytic behaviour
Hazardous reagents
TU/e technische universiteit eindhoven
[email protected] December 2009
RING EXPANSION WITH DIAZO
N
O
Boc
+O
OEtN2
BF3Et2O
N
O OEt
O
• Conventional scaling-up of the reaction of N-Boc-4-piperidine was not possible despite 90% yield under strongly cooled conditions (-25°C).
• Intolerable temperature rises up to 45°C and reactor overpressurisation
• Safe micro processing at 89% yield and only 1.8 min
Hazardous reagents
X. Zhang, S. Stefanick, F.J. Villani, Org. Process Res. Dev. 8, 3 (2004) 455.
TU/e technische universiteit eindhoven
[email protected] December 2009
ENERGY SAVINGS FOR THE PHENYL BORONIC ACID PROCESS
-60
-40
-20
0
20
40
60
80
Conventionalbatch processing
Tem
pera
ture
[ °C]
Solution at AT
RefluxTHF
DistillationTHF
Cryogenicreaction
Hydrolysisat AT
Filtration; extraction
Microreactorprocessing
V. Hessel, C. Hofmann, H. Löwe, A. Meudt, S. Scherer, F. Schönfeld, B. Werner, Org. Proc. Res. Dev. 8, 3 (2004) 511-523
H3CO OCH3
OCH3
MgBr + BOCH3
OCH3B
OH
OHH2O, H+
H3C OHB
Solution at AT
Better product selectivity by 25%
Cleaner raw product by 10%
Process simplification
TU/e technische universiteit eindhoven
[email protected] December 2009
Cost and Environmental Impacts– Cost and Life-Cycle Analysis
TU/e technische universiteit eindhoven
[email protected] December 2009
S. Hübschmann, D. Kralisch, V. Hessel, U. Krtschil, C. Kompter Chem. Eng. Technol. 32, 11 (2009) on-line.
(Simplified) Life-Cycle Analysis
“Do not lock the stable door after the horse has bolted"
Check for competitiveness
“Be holistic"
V. Hessel Chem. Eng. Technol. 32, 11 (2009) on-line.
“Early bird" – ex-ante
‘”EARLY-BIRD MEASURING RODS’ AND BE HOLISTIC
TU/e technische universiteit eindhoven
[email protected] December 2009
COST ANALYSIS FOR COMMERCIAL MICROREACTOR PROCESS AS IS
U. Krtschil, V. Hessel, D. Kralisch, G. Kreisel, M. Küpper, R. Schenk Chimia 60, 9 (2006) 611-617.
Variable Costs, 63%
Remaining fixedCosts, 33%
Product relatedCosts, 4%
Variable Costs
Energy con-sumption, 0.6%
Operator's salary, 32.1%
Total Costs
Disposalcosts, 1.5%
Reagents, 65.8%
TU/e technische universiteit eindhoven
[email protected] December 2009
92.10 € / kgµ-REAC PLANT – 1 reactor; 4.4 t/a; 10 l/h45% selectivity; 200°C / 40 bar (‚high-p,T‘)
µ-REAC PLANT – 1 reactor; 4.4 t/a; 10 l/h70% selectivity; 200°C / 40 bar (‚high-p,T‘)
56.95 € / kgµ-REAC PLANT – 1 reactor; 44 t/a; 100 l/h45% selectivity; 200°C / 40 bar (‚high-p,T‘)
78.43 € / kg
57.47 € / kgµ-REAC PLANT – 10 reactors; 44 t/a; 100 l/h45% selectivity; 200°C / 40 bar (‚high-p,T‘)
107.05 € / kgBATCH-REACTOR PLANT – 20 l; 4.3 t/a45% selectivity; 100°C / 1 bar (‚Reflux‘)
17,352.52 € / kgµ-REAC PLANT – 1 reactor; 0.01 t/a; 0.025 l/h45% selectivity; 100°C / 1 bar
Bench-marking
Base case:high-p,T
Withouthigh-p,T
Further PI byhigh-p,T
Externalnumbering-up
Selectivity
985.18 € / kgBATCH-REACTOR PLANT – 1 l; 0.27 t/a45% selectivity; 100°C / 1 bar (‚Reflux‘)
Bench-marking
COSTING ANALYSIS - 2,4-DIHYDROXY BENZOIC ACID SYNTHESIS
U. Krtschil, V. Hessel, D. Kralisch, G. Kreisel, P. Löb, H. Löwe Org. Proc. Res. Dev. (2006) in preparation.U. Krtschil, V. Hessel, D. Kralisch, G. Kreisel, M. Küpper, R. Schenk Chimia 60, 9 (2006) 611-617.
TU/e technische universiteit eindhoven
[email protected] December 2009
HYPOTHETICAL LIQUID-PHASE REACTION AT THE EDGE TO LARGE-SCALE PRODUCTION
0.2 4
2 0
2
4
6
8
10
12
14
16
18
20
100 120 140 160 180 200 220 240 260
Reaction temperature [°C]
Num
bero
f rea
ctor
s
k=0.01 s-1
100°C
k=0.1 s-1
162°C k=1 s-1
249°C
k=0.05 s -1
141°C
250°C and 70 – 150 bar: ‚New Process Windows‘
10,000 t / aA = 4 x 106 l/(mol s) Ea = 5 x 104 J/mol412 Plates35 cm x 25 cm x 50 cm
1.7 Mio Euro
150 kEuro
TU/e technische universiteit eindhoven
[email protected] December 2009
not consideredMAKS: 96 € / kgMicrowave
CHILKS: 258 € / kgCHILKS*: 41 € / kg
CHAKS: 113 € / kg Conventional
Ionic liquidAqueousHeating
Solvent
Raw material 40 € / kg product Labour 42 € / kg product Waste 12 € / kg product Energy 2 € / kg product ------------------------------------------------- Variable costs 96 € / kg product
Raw material 54 € / kg product Labour 41 € / kg product Waste 16 € / kg product Energy 2 € / kg product ------------------------------------------------- Variable costs 113 € / kg product
CH-A-KS
Raw material 202 € / kg product Labour 40 € / kg product Waste 15 € / kg product Energy 1 € / kg product ------------------------------------------------- Variable costs 258 € / kg product
CH-IL-KS Raw material 20 € / kg product Labour 10 € / kg product Waste 11 € / kg product Energy 0.38 € / kg product ------------------------------------------------- Variable costs 41 € / kg product
CH-IL-KS *(20 times lower costs)
M-A-KS
COMPARISON OF VARIABLE COSTS
V. Hessel, D. Kralisch, U. Krtschil, Energy Environm. Sci. (2008) in press.
Cost analysis
TU/e technische universiteit eindhoven
[email protected] December 2009
REACTION TIME IS DETERMING FACTOR NO. 1
Fast reaction processing has much better global warming potentialEfficient use of reactor capacities is prime issue for eco-efficient processing
FABRICATIONCATALYSTS
REACTORS
PLANTS
PROCESSESOH
OH
OH
OH
COOHKHCO3 (aq)OH
OH
OH
OH
COOHKHCO3 (aq)
PROCESSESG
loba
l war
min
gpo
tent
ial
[kg
CO
2/ F
E; 0
.1 k
g pr
oduc
t]
V. Hessel, D. Kralisch, U. Krtschil Energy Environ. Sci. 1, 4 (2008) 467- 478.
Waste waterElectrical energySolvent / ILKHCO3
Resorcinol
Reaction timereduction
Reaction timereduction
S. Huebschmann, D. Kralisch, V. Hessel, U. Krtschil, C. Kompter, Chem. Eng. Technol. 32, 11 (2009) 1757-1765.
TU/e technische universiteit eindhoven
[email protected] December 2009
Energy and raw materials determining factorsNew processing approaches such as use of ionic liquids may provide different, distinct LCA (and costing) patterns – here: overall negative, due to costlymanufacture of ionic liquids (recycling)
Linear extrapolation to productivity 100 g 2,4- dihydroxy benzoic acid
GLOBAL WARMING POTENTIALFABRICATIONCATALYSTS
REACTORS
PLANTS
PROCESSESOH
OH
OH
OH
COOHKHCO3 (aq)OH
OH
OH
OH
COOHKHCO3 (aq)
PROCESSES
Standard
IL Supercritical
S. Huebschmann, D. Kralisch, V. Hessel, U. Krtschil, C. Kompter, Chem. Eng. Technol. 32, 11 (2009) 1757-1765.
TU/e technische universiteit eindhoven
[email protected] December 2009
Dissemination & ExploitationConferences, Symposia, Research Projects, Products
TU/e technische universiteit eindhoven
[email protected] December 2009
Dual pump and injection system
Touch-screen panel
Heater Cooler
X-CUBE™High-temperature, high-pressure bench top flow reactor
200°C and 150 bar
Advantages• Completion of many reactions
in minutes
• Optimization "on the fly"
• Low-volume system: conductance of volatile reactions safely and at high pressure
Suzuki, Sonogashira and Heck couplings, Buchwald reaction, Halogenation, AlkylationDehydration, Esterification, Azide formation
X-CUBE™: NEW COMMERCIAL HIGH-p,T FLOW REACTOR
TU/e technische universiteit eindhoven
[email protected] December 2009
NOVEL PROCESS WINDOWS CET SPECIAL ISSUE
SocietyEconomy
Environment
TU/e technische universiteit eindhoven
[email protected] December 2009
SynTOP CONFERENCE POTSDAM, JUNE 2008: BRIDGING CHEMISTRY AND CHEMICAL ENGINEERING
Syntop (Ökologie): Lebewesen, die in einem bestimmten Biotop gemeinsam vorkommen
TU/e technische universiteit eindhoven
[email protected] December 2009
Reactions under Novel ConditionsConvener: V. Hessel (NL/DE)
Keynote:J.-i. Yoshida (Uni Kyoto)
Topic Lectures:N. Kockmann (Lonza)L. Magna (IFP)H. Lehmann (Novartis)W. Verboom (Uni Twente)D. Kralisch (Uni Jena)
CONGRESS OF THE EUROPEAN ASSOCIATION FOR CHEMICAL AND MOLECULAR SCIENCES (EuCheMS), TURINO, SEPTEMBER 2008
TU/e technische universiteit eindhoven
[email protected] December 2009
Bayer Technology ServicesBASF Evonik-DegussaArkemaRhodia …
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FIVE COMING AND STARTED EU PROJECTS ON FUTURE CHEMICAL FACTORIES